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Microbiology > 2. Interferon > Flashcards

2. Interferon Flashcards

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1
Q

How does HPV affect interferon?

A
  • Antagonists encoded by the virus stop interferon system from working well
  • Interferon usually targets the virus in many ways, but now it can’t effectively
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2
Q

What is the IRF-7 gene and what happens if it is faulty?

A
  • Key player in interferon induction pathway
  • Inherit 2 copies of the faulty gene => doesn’t work well
  • Therefore, can’t produce interferon alpha in response to infection

(heterozygous mutation can be revealed by exome sequencing)

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3
Q

What causes and happens to people with an autosomal recessive IFNAR2 gene condition?

A
  • Deletion causing gene to come out of frame
  • Premature stop codon inserted
  • Defective interferon alpha receptor
  • Can’t respond to interferon produced during infection

(even viruses that have been vaccinated against can manifest)

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4
Q

What is the IRF-3 gene for, and what happens if there is a heterozygous mutation?

A
  • Part of the interferon signalling pathway

* Patients won’t respond well to viruses

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5
Q

What is the most common cause of sporadic encephalitis in the Western world, at what age is it most common and what causes it?

A

Herpes simplex encephalitis
• Most common in childhood, affecting healthy individuals on primary infection with HSV-1
• Associated with inborn errors in at least 6 genes - one or more genes in the interferon cascade are not working
• So interferon not made when the person is affected with HSV (CNS intrinsic interferon response)
• So much virus in the body => goes to part of the body that it normally wouldn’t

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6
Q

Are the proteins and genes involved in the interferon cascade part of our innate or adaptive immunity?

A

All part of our innate immunity

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7
Q

What are interferons?

A
  • Signalling proteins made and released by host cells in response to viruses
  • Soluble factor, which if put onto cells, induces immunity to any virus
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8
Q

What does interferon activate the de novo transcription of, and what does this do?

A

Interferon stimulated genes (ISGs) - induce anti-viral state in cells (prevents more cells getting infected)

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9
Q

How does giving interferon to people with a common cold make them feel?

A
  • Even worse

* Interferon is associated with a lot of the symptoms of viral infection

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10
Q

What are Type I interferons and their 3 functions?

A

Polypeptides secreted from infected cells (include alpha and beta)
• Induce antimicrobial state in both infected and neighbouring cells
• Modulate innate response to promote antigen presentation and NK, but inhibit pro-inflammation
• Activate the adaptive immune response

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11
Q

What is the first interferon to be made?

A

IFN-beta

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12
Q

Describe what initially happens when cells sense a viral infection

A
  • Cells make an interferon response - new copies of IFN-beta
  • IFN-beta diffuses and interacts with receptors on neighbouring cells
  • Switching on of genes in these cells to put them into an anti-viral state
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13
Q

What are plasmacytoid dendritic cells (PDCs)?

A
  • Specialised cells that are good at making interferon (particularly IFN-alpha)
  • Secretion of type I interferon will recruit APCs and adaptive immune cells
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14
Q

What proportion of cells in the body make type 1 interferons?

A

Nearly every cell

PDCs tend to make IFN-alpha, epithelial cells tend to make IFN-beta

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15
Q

On what tissues is the IFN-alpha receptor (IFNAR) present on?

A

All tissues

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16
Q

What triggers IFN-beta induction?

A

IRF-3

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17
Q

What interferon regulatory factor (IRF) do PDCs express high levels of?

A

IRF-7

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18
Q

How many genes are there for IFN-alpha and beta?

A
  • 13-14 isotopes for IFN-alpha

* 1 gene for IFN-beta

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19
Q

Briefly describe interferon-gamma

A
  • Type II IFN
  • More specialist
  • Produced by immune cells: activated T cells and NK cells
  • Signals through IFNGR
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20
Q

What does IFN-λ (lambda) protect, where is it important and what IL receptors does it signal through?

A
  • Protects the barriers of your body e.g. respiratory and gut epithelium
  • Important in the liver e.g. hepatitis
  • Signals through IL-28 and IL-10β receptors
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21
Q

Which interferons are made when epithelial cells are infected?

A

IFN-lambda and IFN-alpha/beta

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22
Q

What are polymorphism in IFN-lambda associated with?

A

Improved outcome from Hepatitis B (HBV) and C (HCV)

Better clearance and response to antiviral therapy

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23
Q

What is the one thing that a virus cannot hide, that can be detected by our cells?

A

Its nuclei acid

24
Q

What are PAMPs?

A

Pathogen associated molecular patterns (unique to the pathogen)

25
Q

What are PRRs?

A

Pattern recognition receptors -sense foreign nuclei acids via specific receptors:
• RLRs: cytoplasmic RIG-I like receptors
• TLRs: endosomal Toll-like receptors

(there are also cytoplasmic nucleotide oligomerisation domain receptors - NLRs)

26
Q

Do TLRs, RIGs and cGASs detect RNA or DNA?

A

TLR + RIG = RNA

cGAS = DNA

27
Q

Where are TLRs found in the cell?

A
  • Membrane protein

* Found on plasma membrane and endosomal membranes

28
Q

What do RLRs sense and do?

A
  • Sense viruses in the cytoplasm

* Send signal through a mitochondrial located pathway

29
Q

When a virus comes in and makes some RNA, what is this detected by and what does this do (PRR=>Mavs)?

A
  • One of the PRRs - RIG-I or Mda-5, that sits in the cytoplasm
  • Upon binding to viral RNA, they change shape and unfold to interact with a second molecule sitting on the mitochondria - Mavs (mitochondrial activated virus signaller)
30
Q

What happens when Mavs are activated (Mavs => response beginning)?

A
  • Sends a signal - phosphorylating IRF-3 and 7
  • IRF-3 and 7 moves into the nucleus and attaches to the promoter of the IFN-beta gene
  • New synthesis of mRNA for IFN-beta
  • New IFN-beta (and alpha) made, response begins

(IFN-beta is released from these cells and travels to neighbouring cells)

31
Q

What happens if a viral ssRNA is detected inside an endosome of a cell?

A
  • TLR-7 will recognise it
  • Signal to a molecule outside the endosome - MyD88
  • Phosphorylate IRF-3 and 7
  • Expression of IFN-alpha and beta
32
Q

Are the nucleic acids of a virus exposed inside an endosome of a cell?

A

Yes (at some point in their life cycle they will be inside an endosome too)

33
Q

What enzyme detects viral DNA in the cytoplasm, and how does it lead to the production of IFNs?

A

cGAS
• binds to DNA (double stranded)
• synthesises cGAMP
• cGAMP binds to STING in the endoplasmic reticulum
• STING moves into the nucleus to transcribe IFNs (like IRF-3/7)

34
Q

What effect is IFN-beta acting on cells called?

A

Paracrine effect - on neighbouring cells

Autocrine effect - on same cell

35
Q

What kind of receptor is the IFN-alpha/beta and gamma receptor?

A

Alpha/beta - Heterodimeric receptor composed of IFNAR1 and IFNAR2

Gamma - Heterodimeric receptor composed of IFNGR1 and IFNGR2

36
Q

Describe everything that happens when an IFN binds to the IFN-alpha/beta receptor

A
  • Activates Jak and Tyk
  • This phosphorylates STAT1 and STAT2
  • STAT molecules dimerise and combine with IRF9
  • This goes to the nucleus and binds to a responsive promoter region
37
Q 
What do the following interferon stimulated genes do:
• Protein kinase R
• 2'5'OAS
• Mx
• ADAR
• Serpine
• Viperin
A
  • Protein kinase R - inhibits translation (host makes no new host or viral RNA - cell and viral death)
  • 2’5’OAS - activates RNAse L - destroys ssRNA
  • Mx - inhibits incoming viral genomes
  • ADAR - induces errors during viral replication
  • Serpine - activates proteases
  • Viperin - inhibits viral budding
38
Q

What is IFN-induced transmembrane protein (IFITM3) and why is it important?

A

• ISG (interferon stimulated gene)
• Sits on the membrane of endosomes, in cells stimulated with IFN
• When IFITM3 is overexpressed, the membranes of the endosomes become very rigid
- virus cannot escape
• e.g. flu virus enters cell through endosome so IFITM3 can prevent injection of DNA into nucleus

39
Q

Where is IFITM3 deficiency common and what does this mean?

A
  • Parts of Asia (China and Japan)

* More risk of hospitalisation

40
Q

How does Mx1 work?

A
  • Sits on cytoplasm of cells
  • Traps viruses just as they are releasing their nuclei acid
  • Forms multimers which wrap around the nucleocapsids of incoming viruses
  • Useful for flu viruses
41
Q

What is Mx2 important in?

A

Prevents injection of HIV RNA into the nucleus of a cell

42
Q

What protein family is Mx a member of?

A

Dynamin and large GTPases

43
Q

How long does the antiviral state sustained by IFN last and why?

A
  • Several hours, maybe a day
  • Ability to respond to IFN is lost due to negative feedback
  • SOCS (suppressor of cytokine signalling) genes turn off the response
44
Q

How have viruses evolved to evade the IFN response?

A
  • Hiding the PAMP (inside capsule?)
  • Interfere with host cell gene expression
  • Block IFN induction cascades - destruction or binding
  • Block individual IFN induced antiviral enzymes
  • Activate SOCS
  • Develop a replication strategy that is insensitive to IFN e.g. replicate very quickly
45
Q

How does HCV control/evade IFN?

A

Has NS3/4 protease - acts as antagonist to IFN induction by cleaving Mavs

46
Q

How does influenza control/evade IFN?

A

Has NS1 protein - acts as antagonist to IFN induction by binding to and preventing formation of RIG-I/TRIM25/RNA complex - prevents activation of signalling pathway

Also can enter the nucleus and stop IFN-beta mRNA from being exported

47
Q

How do Pox viruses interfere with IFN?

A

Large DNA virus
• More than half of genome is comprised of accessory genes that modify immune response
• Encode soluble cytokine receptors which mop up IFN
• IFN can’t interact with receptor
• IFN and other cytokines are produced in abundance and contribute to the pathology

48
Q

How does the Ebola virus interfere with IFN?

A

• RIG-I and Mda-5 sense the virus
• Ebola produces:
- VP35 - blocks signalling cascade, inhibits the RIG-I pathways
- VP24 - blocks the signal from the IFN receptor into the nucleus, STAT1 can’t enter nucleus (ISGs can’t be transcribed)

49
Q

How does the effect of a virus that has co-evolved with a host for a long time, compare with a virus that has recently crossed from an animal species?

A
  • Co-evolved - balance between its own genes and what the host is trying to do to the virus - controlled and not a lot of bystander damage by immune response
  • New virus - lots of responses switched on, damaging the host cells - nothing in harmony
50
Q

Can interferon be dangerous?

A
  • Viruses can skew the immune response to increase their own replication and transmission
  • Too much interferon can be released - triggers pro-inflammatory pathways
  • High levels of IFN is accompanied by massive release of TNF alpha and other cytokines e.g. in dengue haemorrhagic fever
  • Virus is not controlled either, which leads to more IFN release
  • Levels can vary from protective to immunopathologic
  • Patient can succumb to immune pathology rather than virus
51
Q

How can a cytokine storm affect the lungs?

A

Accumulation of immune cells in the lung spaces => pulmonary fibrosis

52
Q

Why isn’t it common to use interferon as a broad spectrum antiviral?

A
  • Bad if there is too much (dose has to be right)

* Many unpleasant side effects - stimulated TNF-alpha, IL-6 etc. which makes the patient feel awful

53
Q

Why could it be useful to use IFN-lambda as an influenza therapeutic agent?

A
  • Only present on epithelial surfaces
  • Cannot signal through receptors present on immune cells - NO IMMUNE RESPONSE
  • Don’t have side-effects of immunopathology and inflammation
  • Can still induce antiviral state in epithelial target cells
54
Q

When can cells deficient in an IFN response be useful in medicine?

A

Used to grow attenuated virus strains for vaccines

55
Q

What is the downside to engineering a virus for a vaccine, in a way that it can’t control the IFN system, and what is the solution to this?

A
  • Difficult to propagate the virus sufficiently to produce enough virus for loads of vaccines
  • Solution: culture cells that are genetically engineered to be deficient in the IFN response
56
Q

How can we take advantage of the fact the cancer cells are in an IFN deficient state?

A

Oncolytic viruses
• Give them a virus throughout the body
• Virus won’t be able to fight the IFN response
• Only replicates in and kills cancer cells, that are IFN deficient

Microbiology (6 decks)

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